Altered Anterior-Posterior Connectivity Throughthe Arcuate Fasciculus in Temporal Lobe Epilepsy

Shigetoshi Takaya,1,2* Hesheng Liu,1,2 Douglas N. Greve,1,2 Naoaki Tanaka,1,2

Catherine Leveroni,2,3 Andrew J. Cole,2,4 and Steven M. Stufflebeam1,2

1MGH/HST Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts GeneralHospital, Charlestown, Massachusetts

2Harvard Medical School, Boston, Massachusetts3Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts4Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts

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Abstract: How the interactions between cortices through a specific white matter pathway change duringcognitive processing in patients with epilepsy remains unclear. Here, we used surface-based structuralconnectivity analysis to examine the change in structural connectivity with Broca’s area/the right Broca’shomologue in the lateral temporal and inferior parietal cortices through the arcuate fasciculus (AF) in 17patients with left temporal lobe epilepsy (TLE) compared with 17 healthy controls. Then, we investigatedits functional relevance to the changes in task-related responses and task-modulated functional connectivi-ty with Broca’s area/the right Broca’s homologue during a semantic classification task of a single word.The structural connectivity through the AF pathway and task-modulated functional connectivity with Bro-ca’s area decreased in the left midtemporal cortex. Furthermore, task-related response decreased in the leftmid temporal cortex that overlapped with the region showing a decrease in the structural connectivity. Incontrast, the region showing an increase in the structural connectivity through the AF overlapped withthe regions showing an increase in task-modulated functional connectivity in the left inferior parietal cor-tex. These structural and functional changes in the overlapping regions were correlated. The results sug-gest that the change in the structural connectivity through the left frontal–temporal AF pathway underliesthe altered functional networks between the frontal and temporal cortices during the language-relatedprocessing in patients with left TLE. The left frontal–parietal AF pathway might be employed to connectanterior and posterior brain regions during language processing and compensate for the compromised leftfrontal–temporal AF pathway. Hum Brain Mapp 37:4425–4438, 2016. VC 2016 Wiley Periodicals, Inc.

Key words: Broca’s area; Freesurfer; function; language; MRI; psychophysiological interaction; reorga-nization; semantic; structure; tractography

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*Present address: Shigetoshi Takaya is currently at Human BrainResearch Center, Department of Neurology, Kyoto UniversityGraduate School of Medicine, Kyoto 606-8507, Japan

Additional Supporting Information may be found in the onlineversion of this article.

Contract grant sponsor: National Institute of Health; Contractgrant numbers: R01-NS069696, P41-EB015896, U01-MH093765,T32-EB001680; Contract grant sponsor: National Science Founda-tion grant; Contract grant number: NFSDMS-1042134; Contractgrant sponsors: Uehara Memorial Foundation, the SNMMI

(Wagner-Torizuka Fellowship); Contract grant sponsor: Depart-ment of Energy; Contract grant number: DE-SC0008430

*Correspondence to: Shigetoshi Takaya, Human Brain Research Cen-ter, Department of Neurology, Kyoto University Graduate School ofMedicine, Kyoto 606-8507, Japan. E-mail: shig.t@kuhp.kyoto-u.ac.jp

Received for publication 25 April 2016; Revised 4 July 2016;Accepted 7 July 2016.

DOI: 10.1002/hbm.23319Published online 25 July 2016 in Wiley Online Library(wileyonlinelibrary.com).

r Human Brain Mapping 37:4425–4438 (2016) r

VC 2016 Wiley Periodicals, Inc.

INTRODUCTION

Epilepsy affects both structural and functional brain net-works. In temporal lobe epilepsy (TLE), despite the local-ized epileptic focus, a widespread involvement ofstructural and functional brain networks beyond the focushas been demonstrated in neuroimaging studies [Arnoldet al., 1996; Besson et al., 2014; Focke et al., 2008; Haneefet al., 2012; Keller and Roberts, 2008; Voets et al., 2012]. Inconcert with the extensive structural and functional abnor-malities in the brain, patients with TLE exhibit a widerange of cognitive morbidity [Bartha-Doering and Trinka,2014; Hermann et al., 1997; Oyegbile et al., 2004]. Previousstudies have shown that neuropsychological measure-ments of memory, executive function, language abilities,and general intelligence in patients with TLE are correlat-ed with structural changes in the white matter pathway,as measured with diffusion magnetic resonance imaging(MRI) [Diehl et al., 2008; McDonald et al., 2008a; McDo-nald et al., 2014; Riley et al., 2010; Winston et al., 2013;Yogarajah et al., 2008], and functional changes in the cor-tex, measured with [18F]-fluorodeoxyglucose positronemission tomography (PET) [Jokeit et al., 1997; Takayaet al., 2006; Trebuchon-Da Fonseca et al., 2009] and func-tional MRI (fMRI) [Protzner et al., 2013; Protzner andMcAndrews, 2011; Sanju�an et al., 2013].

Although these lines of evidence indicate that the struc-tural changes in the white matter and the functionalchanges in the cortex are both associated with cognitiveperformance in patients with TLE, the relationshipbetween the structural and functional changes during cog-nitive processing remain poorly understood. Given thatthe functional interaction between remote cortices duringcognitive processing is mediated by the structural networkin the white matter, structural changes in an associationpathway may affect task-related regional cortical responseas well as task-modulated functional connectivity in theremote cortices that are connected through this pathway.Investigating the functional relevance of a specific associa-tion pathway may provide insights into the neurobiologi-cal substrates of a broad spectrum of cognitive and

emotional alterations that significantly affect the quality oflife in patients with TLE [Giovagnoli and Avanzini, 2000;Helmstaedter et al., 2003].

The arcuate fasciculus (AF) is a major association path-way in the human brain, which is considered to mediatefunctional connections between remote cortices in anteriorand posterior brain regions during language-related proc-essing. The recent advent of diffusion MRI tractographyenabled us to visualize the trajectory and microstructuralproperties of the AF in the living human brain [Dick andTremblay, 2012]. The AF pathways connecting Broca’sarea/the right Broca’s homologue can be divided into twosubcomponents, one projecting to the temporal cortex(frontal–temporal AF pathway) and the other to the parie-tal cortex (frontal–parietal AF pathway). In healthy sub-jects, the volume of the frontal–temporal AF pathway islarger in the left hemisphere while that of the fron-tal–parietal AF pathway is larger in the right hemisphere[Catani et al., 2007; Catani et al., 2005; Makris et al., 2005;Parker et al., 2005; Powell et al., 2006; Thiebaut de Schot-ten et al., 2011]. In patients with TLE, structural changesin the AF pathway occur. In particular, the frontal–tempo-ral AF pathway ipsilateral to the epileptic focus is vulnera-ble, and a decrease in volume and changes inmicrostructural properties have been commonly reported(Ahmadi et al., 2009; Govindan et al., 2008; Imamura et al.,2015; Kucukboyaci et al., 2012; Lin et al., 2008; McDonaldet al., 2008a). However, the specific cortical regions thathave changed structural connectivity with the AF inpatients with TLE remain unclear. Clarifying these regionswould allow examination of the changes in functionalinteractions between two remote cortices that are con-nected through this pathway.

Functional changes in language-related cortices havealso been observed in patients with left TLE. Activity dur-ing language tasks decreases in the conventional language-related cortices in the left hemisphere, while additionalareas are activated in both hemispheres [Adcock et al.,2003; Billingsley et al., 2001; Br�azdil et al., 2005; Janszkyet al., 2006; Powell et al., 2007; Thivard et al., 2005; Voetset al., 2006]. Although multiple factors could contribute tothe change in cortical activity during language tasks, it hasbeen suggested that patients with left TLE may have diffi-culty in recruiting the normal neural networks [Thivardet al., 2005] and the alternative network may be involved[Gaillard et al., 2011]. Considering that the frontal–tempo-ral AF pathway connecting the anterior and posteriorlanguage-related cortices is a vulnerable pathway in leftTLE, the change in structural connectivity through thispathway in the left hemisphere may underlie the changein cortical activity during language tasks in the these corti-cal regions. In addition, if there is another AF pathwaythat increases in structural connectivity, this pathway maybe employed to compensate for the compromised left fron-tal–temporal AF pathway during language processing.More specifically, the frontal–temporal AF pathway in the

Abbreviations

ADC Apparent diffusion coefficient,AF Arcuate fasciculus,fMRI Functional MRI,FWHM Full-width half-maximum,MD Mean diffusivity,MPRAGE Magnetization-prepared rapid-acquisition gradient-

echo,MRI Magnetic resonance imaging,PET Positron emission tomography,PPI Psychophysiological interaction,TE Echo time,TLE Temporal lobe epilepsy,TR Repetition time

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right hemisphere or the frontal–parietal AF pathways ineach hemisphere might be employed to connect the anteri-or and posterior brain regions.

Here, we examined the structural connectivity of the AFand its functional relevance during a language task inpatients with left TLE. We first examined the change instructural connectivity with Broca’s area/the right Broca’shomologue through the AF in the inferior parietal and lat-eral temporal cortices in patients with left TLE, using asurface-based structural connectivity analysis that we havedeveloped [Takaya et al., 2015]. This method allows visual-izing the cortical regions that show changes in structuralconnectivity of a specific fiber pathway. We then examinedthe association between changed structural connectivity ofthe AF and changes in task-related regional response andtask-modulated functional connectivity during a languagetask in patients with left TLE. Task-modulated functionalconnectivity with Broca’s area/the right Broca’s homologuewas evaluated using psychophysiological interaction (PPI)[Friston et al., 1997]. Some previous studies have comparedstructural changes in the white matter with functionalchanges during language tasks in the cortex in healthy sub-jects as well as patients with TLE [Perlaki et al., 2013; Pow-ell et al., 2007]. However, these studies have extractedindices that reflect the microstructural properties from thewhite matter and compared them with task-related corticalactivity. In contrast, the advantage of our method is that itallows direct comparison of structural connectivity, as mea-sured using diffusion MRI, and cortical function, as mea-sured using fMRI, within the same cortical space. Toevaluate cortical function during cognitive processing, weused a single-word semantic classification task that isknown to activate both Broca’s area and the lateral tempo-ral cortex in the left hemisphere. This task is used to identi-fy the language-dominant hemisphere prior to temporallobectomy and is thought to require functional interactionbetween the frontal and temporal language-related cortices,purportedly through the AF [Demb et al., 1995; Desmondet al., 1995; Glasser and Rilling, 2008; Takaya et al., 2015;Wang et al., 2014; Whitney et al., 2011].

We expected that structural and functional connectivitybetween the anterior and posterior language-related corti-ces would be altered in patients with TLE, even if nostructural lesion was present in these neocortical regions.Therefore, we excluded patients with structural abnormali-ties between the anterior and posterior ends of the AF,including altered cortical thickness in the lateral temporaland inferior parietal cortices, which is often observed inpatients with TLE [Bernhardt et al., 2010; McDonald et al.,2008b; Mueller et al., 2009].

MATERIAL AND METHODS

Subjects

We initially recruited 20 right-handed patients withmedically intractable left TLE and no concomitant

neurological and psychiatric diseases. Patients with neo-cortical or white matter lesions that were visually detectedon conventional MRI were then excluded. We also mea-sured cortical thickness using a computer-based automat-ed algorithm (see data analysis), and excluded patientswith altered cortical thickness in the lateral temporal andinferior parietal regions (outside the mean 62 SD ofhealthy controls). Based on these criteria, we excluded 3patients out of the initial 20. We also recruited right-handed healthy controls from the community who werefree from neurological and psychiatric diseases. Thus, weexamined 17 patients (mean age 6 standard deviation:31.7 6 11.1, nine male) and 17 healthy controls (meanage 6 standard deviation: 29.7 6 11.5, 6 male). The handed-ness was assessed using the Edinburgh HandednessInventory. There was no significant difference betweengroups in terms of mean age (P 5 0.61, two sample t-test)and sex (P> 0.49, Fisher’s exact test). Patients had com-pleted a comprehensive evaluation for epilepsy surgeryand received a clinical diagnosis of left TLE based onseizure semiology, electroencephalography, and neuroim-aging. All patients underwent long-term video electroen-cephalography monitoring and conventional MRI. Three of17 patients showed atypical language lateralization, asassessed by task-activation fMRI [Labudda et al., 2012].None of healthy subjects showed atypical language lateral-ization. The clinical information of all patients is listed inTable I. The study was approved by the institutionalreview board of our institution and each subject providedwritten informed consent.

Imaging Data Acquisition

All MRI data were acquired on a 3 Tesla Siemens TimTrio scanner (Erlangen, Germany). A high-resolutionthree-dimensional structural image was acquired usingmagnetization-prepared rapid-acquisition gradient-echo(MPRAGE) sequence (voxel size: 1 3 1 3 1 mm; repetitiontime (TR): 2,000 ms; echo time (TE): 3.37 ms; flip angle:108). Diffusion-weighted data were acquired using echoplanar imaging (voxel size: 2 3 2 3 2 mm; diffusionweighting isotropically distributed along 60 directions; bvalue: 700 s/mm2).

Three runs of task-activation fMRI data were acquiredusing a language task involving the semantic classificationof written words. Images were acquired using a gradient-echo sequence (voxel size: 3 3 3 3 3 mm; TR: 2,000 ms;TE: 30 ms; flip angle: 908; slice gap: 0.6 mm). Each runconsisted of one 8-s initial block that was discarded toallow for T1-equilibration effects, followed by a 28-s fixa-tion block and then a 36-s task block. There were threesuch fixation/task blocks. During the task blocks, 12words (six concrete and six abstract words) were pre-sented in random order for 2 s each with a 1-s interstimu-lus interval. In total, 108 stimuli were presented.Participants were asked to indicate if the word was

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concrete or abstract without articulating by pressing a keyon a keyboard (left-hand key press for abstract words,right-hand key press for concrete words).

Imaging Data Analysis

Anatomical analysis

The structural MRI was analyzed in FreeSurfer (FS) ver-sion 5.3 (surfer.nmr.mgh.harvard.edu). FS creates a meshmodel of the cortex as well as a thickness measurement[Fischl and Dale, 2000] and region label at each point inthe cortex [Desikan et al., 2006]. It also provides surface-based intersubject registration [Dale et al., 1999; Fischlet al., 1999]. The FS anatomical analysis was used as a sub-strate for the integration of structural connectivity andfMRI results by mapping each of those results to a com-mon surface-based coordinate system.

Cortical thickness measurement

Cortical thickness estimation was obtained using FS. Thedetailed procedures are described elsewhere [Fischl andDale, 2000]. Briefly, after an automated procedure includ-ing skull-stripping, intensity normalization, and segmenta-tion of subcortical white matter and deep gray matterstructures, a single white matter volume for each

hemisphere was obtained and covered with a polygonaltessellation. The cortical thickness at each vertex across thecortical mantle was defined by the shortest distancebetween the white matter surface (the gray-white bound-ary) and the pial surface (the gray-CSF boundary) at eachvertex on the tessellated surface. The individual data wereregistered to the averaged cortical surface template of eachhemisphere and smoothing was performed along the sur-face with a 10-mm full-width half-maximum (FWHM)Gaussian kernel.

Surface-based structural connectivity analysis

for the AF

The tractography analysis was performed using FMRIB’sDiffusion Toolbox implemented in FSL version 5.0 (www.fmrib.ox.ac.uk/fsl/fdt). Probabilistic tracts were generatedbetween two FS-defined regions, starting from the gray-white matter boundary surface of the lateral temporal andinferior parietal cortices (seed) and terminating at theboundary surface of Broca’s area/the right Broca’s homo-logue (target, defined as the pars opercularis and pars tri-angularis); see Figure 1. Symmetric inclusion masks weredefined in the white matter of a standard volume space(MNI 152) and registered onto the native space of eachsubject. The white matter inclusion mask for the left AFwas located in a standard space (MNI 152) at the level of asingle coronal slice at y 5 28, extending from x 5 228 to

Figure 1.

Seed and target regions and white matter inclusion

masks for the structural connectivity analysis of the

arcuate fasciculus. Top and bottom figures: Seed (yellow)

and target (green) regions at the gray-white matter boundary

surface in each hemisphere of an individual brain. Middle fig-

ures: The symmetric white matter inclusion masks defined in

each hemisphere of a standard space (blue).

Figure 2.

Group-averaged images of the structural connectivity

with Broca’s area/the right Broca’s homologue through

the arcuate fasciculus (AF) in healthy controls (top) and

patients with left TLE (bottom) on the averaged gray-

white matter boundary surface. The normalized connection

probability is rescaled for display purposes. a.u.: arbitrary unit.

r Altered Anterior-Posterior Connectivity in TLE r

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248, and z 5 16 to 36. The inclusion mask for the right AFwas created by flipping the masks in the left hemisphere.The exclusion mask consisted of the bilateral thalami, stri-atum, and midline sagittal plane.

The connection probability at a seed voxel was comput-ed as the number of tracts that reached the ipsilateral tar-get region from that seed voxel. The connection probabilityat each voxel was then normalized by dividing it by thetotal number of tracts that reached the target region

through the white matter inclusion mask from the entiregrey–white matter boundary surface in each hemisphere.The normalized connection probability maps of the AFwere sampled from the volume onto the cortical surface ofeach individual’s left and right hemispheres. Individualconnection probability maps on the cortical surface wereregistered to the averaged cortical surface template of eachhemisphere using surface-based alignment. Smoothing wasperformed along the surface with a 10-mm FWHM Gauss-ian kernel (Fig. 2 and Supporting Information Fig. 1). Formore details, see elsewhere [Takaya et al., 2015].

Task-activation fMRI data analysis

Surface-based analysis was conducted for task-activationfMRI data using FS Functional Analysis Stream (FS-FAST).The details are described elsewhere (http://surfer.nmr.mgh.harvard.edu/fswiki/FsFast). Briefly, after the first four vol-umes were discarded to allow for T1-equilibration effects,the fMRI images were motion corrected to the middle timepoint. The middle fMRI time point was registered to the ana-tomical image for each subject using boundary-based regis-tration [Greve and Fischl, 2009] and sampled onto thesurface. Each individual image was registered to the aver-aged cortical surface template of each hemisphere usingsurface-based alignment and smoothed along the surfacewith a 10-mm FWHM Gaussian kernel [Hagler et al., 2006].A general linear model was used to determine the brainregions activated in the word-classification task. A boxcarfunction was convolved with the SPM canonical hemody-namic response function to generate the task regressor. Sixhead motion parameters were used as nuisance regressors.

Task-modulated functional connectivity

To examine whether functional connectivity with Broca’sarea/the right Broca’s homologue changed during the taskin the lateral temporal and inferior parietal cortices inpatients with TLE, task-modulated functional connectivitywas examined using PPI analysis [Friston et al., 1997]. ThePPI first-level analysis model included two psychologicalregressors (task and rest), one physiological regressor (amean time course extracted from Broca’s area/the rightBroca’s homologue) and two interaction terms between thepsychological and physiological regressors. White matter/CSF signal, six head motion parameters, and the effect oftask were regressed using CONN toolbox in Matlab(http://www.nitrc.org/projects/conn/).

Group comparisons

The above steps rendered cortical thickness, the struc-tural connectivity of the AF, task-related regional response,and task-modulated functional connectivity onto the samesurface-based common space where they could be com-pared across subjects and integrated across modalities. Thegroup comparisons for these measurements were

Figure 3.

Group comparison. (A) Clusters showing significant patient-

control differences in the structural connectivity with Broca’s

area/the right Broca’s homologue through the arcuate fasciculus,

(B) task-related regional response, and (C) task-modulated

functional connectivity with Broca’s area/the right Broca’s homo-

logue during a semantic classification task. The results are dis-

played on an inflated surface of the average brain. Group

comparison analyses were carried out within the inferior parie-

tal and lateral temporal cortices (yellow-outlined region). Darker

and lighter regions on the inflated surface denote the sulci and

gyri, respectively.

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performed using a vertex-wise two-sample t-test betweenpatients and healthy controls. We constrained the groupcomparison for task-activation fMRI and cortical thicknessmeasurement within the same region that was used in thestructural connectivity analysis, i.e., the lateral temporaland inferior parietal cortices (yellow outlined region inFig. 3 and Supporting Information Figs. 2 and 3). Task-modulated functional connectivity with Broca’s area andthat with the right Broca’s homologue were evaluatedwithin the left and right lateral temporal and parietal corti-ces, respectively. Clusters were defined using a vertex-wise threshold of P< 0.05. Cluster-based correction formultiple comparisons was performed using a Monte Carlosimulation within this region [Hagler et al., 2006].

Structure–function relationship

We overlaid the results of group comparisons onto thesame surface-based common space and examined theirspatial relationship. To further examine the structur-e–function relationship, we calculated Spearman’s correla-tions using the measurements of structural connectivity,task-related response, and task-modulated functional con-nectivity of each subject. From the spatially overlappingregions, we extracted the normalized connection probabili-ty of the AF for structural connectivity, percent signalchanges adjusted by the global response (the mean percentsignal change over the entire cortex in the same hemi-sphere) for task-related regional response, and regressioncoefficients for task-modulated functional connectivity.

RESULTS

The structural connectivity with Broca’s area/the rightBroca’s homologue through the AF decreased in the left

midtemporal cortex (the middle of the superior temporalsulcus), and increased in the left inferior parietal cortex(the posterior part of the supramarginal gyrus) and theright midtemporal cortex (the middle of the superior tem-poral sulcus) in patients with left TLE as compared tohealthy controls (Fig. 3A and Table II). The language-taskrelated response decreased in the left midtemporal cortex(the middle of the superior temporal sulcus) and the leftinferior temporal cortex (the posterior fusiform gyrus),and increased in the right inferior parietal cortex (the pos-terior part of the supramarginal gyrus and anterior part ofthe angular gyrus) in patients (Fig. 3B and Table II). Task-modulated functional connectivity with Broca’s areadecreased in the left midtemporal cortex (the middle ofthe superior temporal sulcus) and increased in the leftinferior parietal cortex (the supramarginal gyrus) and thatwith the right Broca’s homologue decreased in the rightinferior parietal cortex (the anterior part of the angulargyrus) in patients (Fig. 3C and Table II).

The brain region showing a decrease in the structuralconnectivity of the AF overlapped with the region show-ing a decrease in task-related response in the left midtem-poral cortex (Fig. 4A left). There was a positive correlationbetween the structural connectivity and task-relatedresponse in the overlapping region (Spearman’s rho 5 0.36,P 5 0.037; Fig. 4A right). The region showing an increasein the structural connectivity of the AF partially over-lapped with the brain region showing an increase in task-modulated functional connectivity with Broca’s area in theleft inferior parietal cortex (Fig. 4B left). There was a posi-tive correlation between the structural connectivity andtask-modulated functional connectivity in the overlappingregion (Spearman’s rho 5 0.40, P 5 0.020; Fig. 4B right).

The vertex-wise group analysis of cortical thicknessmeasurements indicated that no significant thinning or

TABLE II. Brain regions showing significant increases and decreases in structural connectivity,

task-related response and task-modulated functional connectivity

Side Region

Peak coordinatea

Size (mm2) Peak P valuex y z

Structural connectivity

Decrease L STS 250 242 22 691 < 5 3 1023

Increase L SMG 250 246 45 1035 < 5 3 1024

R STS 66 232 212 820 < 5 3 1022

Task-related response

Decrease L STS 248 239 22 978 < 5 3 1027

L ITS 246 236 224 799 < 5 3 1024

Increase R SMG 52 244 35 812 < 5 3 1025

Task-modulated functional connectivity

Decrease L STS 253 212 218 402 < 5 3 1024

R AG 47 253 25 685 < 5 3 1024

Increase L SMG 244 236 42 850 < 5 x 1025

AG: angular gyrus; ITS: inferior temporal sulcus; SMG: supramarginal gyrus; STS: superior temporal sulcus.aMNI coordinate.

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thickening was found within these regions in patients(Supporting Information Fig. 2). Even when two patientswhose epileptic focus was not determined in the medialtemporal lobe or three patients who had atypical languagelateralization were excluded from the analyses (PatientNo. 5 and 15, and Patients No. 5, 11 and 13 in Table I,respectively), the results were substantially unaltered(Supporting Information Fig. 3).

DISCUSSION

In summary, surface-based analysis based on probabilis-tic tractography showed that the structural connectivitywith Broca’s area/the right Broca’s homologue throughthe AF decreased in the left midtemporal cortex andincreased in the left inferior parietal and right midtempo-ral cortices in patients with left TLE. Taking advantage ofa surface-based method that enabled us to map the resultsacross modalities on the same surface-based commonspace, we compared changes in the structural connectivityof the AF with changes in task-related regional responsesand task-modulated functional connectivity with Broca’sarea/the right Broca’s homologue during a semantic classi-fication task of a single word. In particular, structuralchanges were associated with functional changes in thesame regions in the midtemporal and inferior parietal cor-tices in the left hemisphere.

Changes in Structural Connectivity Through the

AF in the Temporal and Parietal Cortices

The structural connectivity with Broca’s area throughthe left frontal–temporal AF pathway decreased in the leftmidtemporal cortex in patients with left TLE. A widelydistributed change in white matter has been reported inpatients with TLE [Bernasconi et al., 2004; Focke et al.,2008]. Previous diffusion MRI tractography studies haveshown that the volume and integrity of the white matterpathways connecting the frontal and temporal language-related cortices are decreased in patients with TLE [Powellet al., 2007]. Among these pathways, the AF ipsilateral tothe epileptic focus is highly vulnerable [Ahmadi et al.,2009; Govindan et al., 2008; Imamura et al., 2015; Kucuk-boyaci et al., 2012; Lin et al., 2008; McDonald et al., 2008a].Our result extends these previous findings by more specif-ically showing a regional decrease in the structural con-nectivity of the frontal–temporal AF pathway in themiddle of the left superior temporal sulcus in patientswith left TLE. The AF extending to the midtemporal cortexmay be relevant to the evolution of language in the humanbrain because this pathway is absent in nonhuman pri-mates [Rilling et al., 2008]. In addition, this pathway ismore dominant in the left hemisphere than the right hemi-sphere in the healthy human brain [Catani et al., 2007;Takaya et al., 2015]. Our results indicate that the AFextending to the midtemporal cortex, which may play a

substantial role during language-related processing in thehealthy human brain, is likely to be affected in patientswith left TLE.

In contrast, the structural connectivity with the rightBroca’s homologue through the right frontal–temporal AFpathway increased in the right midtemporal cortex in thecurrent study. Regarding the structural changes in theright AF in patients with left TLE, various results havebeen reported in previous studies depending on how thispathway was evaluated. Some studies that used indicesreflecting white matter integrity, such as fractional anisot-ropy (FA), mean diffusivity (MD) and apparent diffusion

Figure 4.

Structure–function relationship. (A) The brain region

showing a decrease in the structural connectivity through the

frontal2temporal arcuate fasciculus (AF) pathway (1� the blue

outlined area; see also the left figure in Fig. 3A) overlaps with

the region showing a decrease in task-related response during

semantic classification task (2� the blue filled area; see also the

left figure in Fig. 3B). Structural connectivity correlates with

task-related response in the overlapping region in the left tem-

poral cortex. (B) The brain regions showing an increase in the

structural connectivity through the frontal2parietal AF pathway

(3� the red outlined area; see also the left figure in Fig. 3A) par-

tially overlaps with the region showing an increase in task-

modulated functional connectivity with Broca’s area during a

semantic classification task (4� the orange filled area; see also

the left figure in Fig. 3C). Structural connectivity correlates

with task-modulated functional connectivity in the overlapping

region in the left parietal cortex. a.u.: arbitrary unit; b: regres-

sion coefficient; rho: Spearman’s correlation coefficient.

r Takaya et al. r

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coefficient (ADC), have claimed damage to the right AF.One such study reported that FA decreased in 9 adultpatients with left TLE although MD was unchanged(McDonald et al., 2008a). Another study reported thatADC increased in 13 children with left TLE although FAwas unchanged [Kim et al., 2011]. In these studies, howev-er, the averaged indices were extracted from the AF thatwas defined using diffusion MRI tractography. Therefore,the results were highly dependent on how the AF wasdefined. In contrast, when the volume of the white matterpathway that connects the right frontal cortex includingthe right Broca’s homologue was evaluated, the white mat-ter volume of the pathway that projects to the temporallobe (corresponding to the right frontal–temporal AF path-way in the current study) increased in seven patients withleft TLE [Powell et al., 2007]. This method is similar to themethod we used in the current study. We confirmed thisprior finding with a larger number of patients and morespecifically delineated a region showing an increase in thestructural connectivity of the frontal–temporal AF pathwayin the middle of the right superior temporal sulcus,approximately in the homologous region showing adecrease in structural connectivity in the left hemisphere.

Animal studies have shown that the brain has the capac-ity to anatomically rewire in the ipsilateral and contralater-al hemispheres in response to brain damage [Chen et al.,2002; Dancause et al., 2005; Stroemer et al., 1995]. Howev-er, the large-scale rewiring of long tracts after brain lesionin the adult human brain has not been well demonstrated.It seems more likely that disease modifies structural orga-nization that occurs during the course of development. Innormal development, the AF shows increased FA anddecreased radial diffusivity, which has been interpreted asthe maturation of this pathway in development [Asatoet al., 2010; Giorgio et al., 2008]. The maturation of thewhite matter pathway might be related to an increase inmyelination that continues to occur through adolescence[Benes, 1989; Yakovlev and Lecours, 1967]. Furthermore, arecent study using post-mortem tissues of the humanbrain demonstrated that synaptic pruning in the prefrontalcortex continues until an individual’s late twenties [Petan-jek et al., 2011]. Therefore, one possible hypothesis thatexplains our findings is that the right AF that connects theright Broca’s homologue and the right midtemporal cortexmight evade the pruning and develop if the left hemi-sphere acquires epileptogenicity during development andthe maturation of the left AF is disturbed.

An increase in structural connectivity through the leftfrontal–parietal AF pathway was also observed in the leftinferior parietal cortex. Contrary to our result, one studyhas shown that the mean FA in the whole trajectory of thispathway did not increase, but decreased in the left hemi-sphere as compared with healthy subjects [Ahmadi et al.,2009]. However, microstructural white matter changessuch as FA are distributed heterogeneously in patientswith TLE. For example, while a decrease in FA has been

observed in the most parts of the white matter in patientswith TLE, an increase in FA has been reported in remotewhite matter pathways that are not directly connectedwith the affected temporal lobe, such as the corpus cal-losum [Meng et al., 2010] and the internal capsule [Wanget al., 2010]. Furthermore, even within a white matterpathway that is connected with the affected temporal lobe,such as the uncinate fasciculus, the inferior longitudinalfasciculus, and the frontal–temporal AF pathway, themicrostructural white matter abnormalities are moreprominent in proximal segments near the affected tempo-ral lobe and taper off in distal segments outside the tem-poral lobe [Concha et al., 2012]. Possible explanations forthese results are that pathological changes are more likelyto occur in the vicinity of the epileptic focus and that theaffected pathway is compensated by intact axons joiningthe pathway in distant regions [Bodini and Ciccarelli,2013]. As an extension of these previous studies, ourresults might indicate that the structural connectivity ofthe left frontal–parietal AF pathway increases in the distalpart of the projection regions from the affected temporallobe.

Functional Changes Through the AF in the

Temporal and Parietal Cortices

Although the role of the frontal and temporal cortices inthe semantic network is highly controversial, the left tem-poral cortex may be essential for the storage of semanticinformation [Binder et al., 2009; Binder et al., 1997; Book-heimer, 2002; Hickok and Poeppel, 2004; Patterson et al.,2007; Vandenberghe et al., 1996; Vigneau et al., 2006; Whit-ney et al., 2011]. In contrast, the left inferior prefrontal cor-tex, including Broca’s area, may serve as a centralexecutive for retrieving and evaluating semantic informa-tion and making decisions, presumably via top-down sig-nals to the temporal cortex [Badre et al., 2005; Binderet al., 1997; Bookheimer, 2002; Demb et al., 1995;Thompson-Schill et al., 1997; Wagner et al., 2001; Whitneyet al., 2011]. In particular, the semantic classification taskrequires functional interaction between Broca’s area andthe left midtemporal cortex, supposedly through the AF[Demb et al., 1995; Glasser and Rilling, 2008; Takaya et al.,2015; Wang et al., 2014; Whitney et al., 2011]. In the cur-rent study, structural and task-modulated functional con-nectivity with Broca’s area decreased in the leftmidtemporal cortices. In addition, task-related regionalresponse decreased in the left midtemporal cortex thatoverlapped with a region showing a decrease in the struc-tural connectivity with Broca’s area through the AF. Fur-thermore, these changes were positively correlated.Therefore, we assume that the change in the structuralconnectivity through the left frontal–temporal AF pathwayalters functional networks between the frontal and tempo-ral cortices in patients with left TLE. This assumption isconsistent with a previously proposed hypothesis that

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patients with left TLE have difficulty in recruiting thefrontal–temporal network in the left hemisphere duringlanguage processing [Thivard et al., 2005]. Our results sup-port this hypothesis and suggest that changed structuralconnectivity of the frontal–temporal AF pathway underliessuch difficulty in recruiting the functional networksbetween the frontal and temporal cortices in patients withleft TLE.

The concomitant structural and functional changes inthe left midtemporal cortex are unlikely to result simplyfrom macroanatomical changes in this region because weexcluded patients with MRI abnormalities, including sig-nificant brain atrophy, in this region. Furthermore, therewas no significant change in cortical thickness in this areain the individual and group analyses. However, micro-scopic neocortical and white matter abnormalities that areundetectable via MRI can be found in the resected tempo-ral lobe specimens of patients with TLE, regardless of thepresence or absence of medial temporal sclerosis [Carneet al., 2004; Kasper et al., 2003; Mitchell et al., 1999]. There-fore, microstructural changes in this cortical region and/orin the white matter between the temporal and frontal cor-tices might have influenced the structural connectivity ofthe AF, task-related regional responses and task-modulated functional connectivity in this region.

Intrahemispheric and interhemispheric functional reor-ganization of the language-related cortices has beenreported in patients with left TLE using various languagetasks in fMRI studies [Adcock et al., 2003; Billingsley et al.,2001; Br�azdil et al., 2005; Janszky et al., 2006; Powell et al.,2007; Thivard et al., 2005; Voets et al., 2006]. The changedcortical response during the tasks may indicate that alter-native networks are involved to compensate for the com-promised brain network, so as to achieve adequate taskperformance [Gaillard et al., 2011]. In the current study,Broca’s area and the left inferior parietal cortex, which arestructurally connected through the frontal–parietal AFpathway, showed an increase both in structural and task-modulated functional connectivity. In addition, there wasa positive correlation between structural and task-modulated functional connectivity. These results suggestthat functional coupling during the language taskincreased between Broca’s area and the left inferior parie-tal cortex through the left frontal–parietal AF pathway inpatients. The left frontal–parietal AF pathway, whichshowed an increase in structural connectivity with Broca’sarea, might be employed to connect the anterior and pos-terior language-related cortices during language process-ing and compensate for the compromised leftfrontal–temporal AF pathway in patients with left TLE.However, in the current study, such increases in structuraland functional connectivity with Broca’s area were notaccompanied by changes in task-related responses in theleft inferior parietal cortex. This might be because of a lackof sensitivity or the variability associated with group anal-ysis. Another possibility is that an increase in functional

coupling with Broca’s area was not effective to induce achange in the task-related cortical response in the left pari-etal cortex.

Contrary to the left hemisphere, structural and function-al changes were mismatched in the right hemisphere. Ithas been shown that in patients with left TLE as comparedwith healthy subjects, the functional response during somelanguage tasks increases in multiple regions in the righthemisphere, including the right Broca’s homologue[Janszky et al., 2006; Voets et al., 2006]. Thus, the righthemisphere is thought to play a substantial role in thereorganization of language function in patients with leftTLE. However, despite a potential compensatory function-al shift of language to the right hemisphere, this hemi-sphere is not as able to process language as the lefthemisphere. Studies of patients who underwent left hemi-spherectomy in their early life have shown that language-related processing in the right hemisphere is not alwayscarried out in the anatomical homologues of the conven-tional language-related cortices in the left hemisphere[Li�egeois et al., 2008; Voets et al., 2006]. In the currentstudy, while the structural connectivity of the AF in theright hemisphere increased in the homologous regionshowing a decrease in the structural connectivity of theAF in the left hemisphere, it was not accompanied bychanges in task-related regional response or task-modulated functional connectivity. Our results indicatethat structural brain networks other than the AF mayunderlie functional reorganization in the right hemisphereto connect the anterior and posterior brain regions duringlanguage processing.

Another point of interest is that task-modulated func-tional connectivity with the right Broca’s homologuedecreased in the right inferior parietal cortex. Studies ofpatients after stroke have shown that the involvement ofthe homologous language network in the right hemispheremay not be optimal for functional recovery after an insultin the left hemisphere [Belin et al., 1996; Rosen et al.,2000]. Furthermore, the suppression of the right homolo-gous network may enhance the recovery of language func-tion [Hamilton et al., 2010; Naeser et al., 2005; Naeseret al., 2011]. In patients with left TLE, an increase in task-modulated functional connectivity between the frontal andparietal cortices in the left hemisphere may enhance func-tional reorganization in combination with a decrease intask-modulated functional connectivity in the right homol-ogous network.

Caveats and Future Studies

Despite the potential implications of our findings forclinical neuroscience, there are caveats regarding ourstudy. First, whether the reorganization of the languagenetwork in patients with left TLE is adaptive or maladap-tive for actual cognitive performance was not addressed.We did not evaluate performance during the fMRI scans

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because our semantic classification task included ambigu-ous words that cannot be simply classified. In addition,we have not recorded neuropsychological measurementsfor all the patients in a consistent manner because the pri-mary purpose of the current study was to examine therelationship between structural changes in the white mat-ter and functional changes in the cortex during a cognitivetask. Further studies are needed to explore the effect ofthe structural-functional reorganization of language net-work on the change in language abilities.

Second, we used a single-word classification task in con-trast to a low-level non-linguistic fixation baseline. Thiscould involve many brain regions that mediate multiplelevels of language processing. Finer-grained fMRI designsand contrasts are needed to investigate structure–functionrelationships during specific aspects of languageprocessing.

Third, our findings were based on cross-sectional groupcomparisons and the direct effect of the epileptic activityon the structure-function relationship through the AF ineach patient remains unclear. Patients with left TLE usual-ly have widespread cognitive morbidity including lowergeneral intelligence, memory, language, and executivefunctions than healthy subjects [Hermann et al., 1997;Oyegbile et al., 2004]. Therefore, the use of different strate-gies when performing the paradigm may affect fMRIresults. In addition, antiepileptic drugs may also influencefMRI results. In order to address these many confoundingfactors, multivariate analyses with a much larger numberof subjects or longitudinal studies to evaluate the effect ofepileptic activity are warranted. Given that the corticaldysfunction at rest that exists among numerous brainregions, as measured by [18F]-FDG PET, improves after theselective removal of the epileptogenic lesion in patientswith TLE [Dupont et al., 2001; Takaya et al., 2009], thetask-related response and task-modulated functional con-nectivity during language-related processing may be ame-liorated in the cortices that are connected through the AFafter epilepsy surgery is carried out without injuring thispathway and patients become seizure free.

CONCLUSIONS

We used surface-based structural connectivity analysisbased on probabilistic tractography and demonstratedaltered structural connectivity with Broca’s area/the rightBroca’s homologue through the AF in the lateral temporaland inferior parietal cortices in patients with left TLE. Tak-ing advantage of this method to map the structural con-nectivity of the AF to the cortex, we then examined therelevance of the change in the structural connectivity ofthe AF to cortical function. Our results suggest that adecrease in structural connectivity with Broca’s areathrough the left frontal–temporal AF pathway underliesthe altered functional networks between the frontal andtemporal cortices during language-related processing in

the left hemisphere in patients with left TLE. In contrast,the left frontal–parietal AF pathway, which showed anincrease in structural connectivity with Broca’s area, mightbe employed to connect anterior and posterior language-related cortices during the task and compensate for thecompromised left frontal–temporal AF pathway in patientswith left TLE. Our study implies that the cortical interac-tion during cognitive processing through specific whitematter pathways is altered in patients with TLE.

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